title: Single nucleotide polymorphisms in arrhythmia genes modify the risk of cardiac events and sudden death in long QT syndrome.
abstract: BACKGROUND
  Disease-modifying single nucleotide polymorphisms (SNPs) can help explain incomplete penetrance and variable expressivity in congenital long QT syndrome (LQTS) by altering susceptibility to arrhythmias.
  
  
  OBJECTIVE
  The purpose of this study was to assess multiple arrhythmia SNPs (in 16 genes) in a distinct cohort of LQTS patients to identify modifier SNPs influencing the risk of sudden death.
  
  
  METHODS
  This study included 273 patients with LQTS from the New Zealand Cardiac Inherited Disease Registry (154 long QT type 1, 96 long QT type 2, and 23 long QT type 3), including 31 patients who had experienced death or resuscitated sudden cardiac death (RSCD). Patients were genotyped for 29 SNPs and tested for associations with clinical events and QTc length. Caucasian (n = 220) and Pacific Islander/New Zealand Maori (n = 53) ethnic groups were analyzed separately. This subgroup of Polynesian ancestry has not been previously studied for LQTS in either presentation or outcome.
  
  
  RESULTS
  In Caucasians, four SNPs at two risk loci (NOS1AP: rs12143842 and rs16847548; and KCNQ1: rs10798 and rs8234) were significantly associated with clinical events after correction for multiple testing. Patients homozygous for the risk allele of rs12143842 had an increased risk of death/RSCD [hazard ratio 10.15, 95% confidence interval (2.38, 43.34), q = 0.045). Several other SNPs showed trends toward association with QTc length and clinical events.
  
  
  CONCLUSIONS
  This study demonstrates that SNPs in NOS1AP and KCNQ1 are associated with an increased risk of cardiac events in LQTS patients, with the hazard ratio suggesting they have significant potential in clinical risk stratification.
authors.affiliation: Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
authors.forename: Nikki
authors.initials: N
authors.lastname: Earle
authors.affiliation: Discipline of Nutrition, School of Medical Science, University of Auckland, New Zealand.
authors.forename: Dug
authors.initials: D
authors.lastname: Yeo Han
authors.affiliation: Christchurch Heart Institute, University of Otago, Christchurch, New Zealand.
authors.forename: Anna
authors.initials: A
authors.lastname: Pilbrow
authors.affiliation: Greenlane Paediatric and Congenital Cardiac Services, Starship Childrens Hospital, Auckland, New Zealand.
authors.forename: Jackie
authors.initials: J
authors.lastname: Crawford
authors.affiliation: Greenlane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Warren
authors.initials: W
authors.lastname: Smith
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Shelling
authors.affiliation: Christchurch Heart Institute, University of Otago, Christchurch, New Zealand.
authors.forename: Vicky
authors.initials: V
authors.lastname: Cameron
authors.affiliation: Diagnostic Genetics, LabPlus, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Love
authors.affiliation: Greenlane Paediatric and Congenital Cardiac Services, Starship Childrens Hospital, Auckland, New Zealand. Electronic address: jskinner@adhb.govt.nz.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Skinner
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D004247:DNA / Q000235:genetics*; D016757:Death, Sudden, Cardiac / Q000453:epidemiology / Q000209:etiology*; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009520:New Zealand / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D055815:Young Adult
chemical_list: D004247:DNA
keywords: Arrhythmia; CI; ECG; GWAS; Genetics; HR; LQT1; LQT2; LQT3; LQTS; Long QT syndrome; NZ; New Zealand; OR; QTc; RSCD; SCD; SNP; Single nucleotide polymorphisms; Sudden cardiac death; confidence interval; corrected QT interval; electrocardiogram; genome wide association study; hazard ratio; long QT syndrome; long QT syndrome type 1; long QT syndrome type 2; long QT syndrome type 3; odds ratio; resuscitated sudden cardiac death; single nucleotide polymorphism; sudden cardiac death